tbuckley/cabot-search huggingface dataset:
Highlights of This Issue
Journal: Clinical Cancer Research (2016)

Substantial benefits can be achieved with crizotinib therapy in ROS1-rearranged lung cancer patients; however, acquired resistance represents an important clinical challenge. Drilon and colleagues report the discovery of a novel ROS1D2033N mutation that emerged after crizotinib therapy in a patient with CD74-ROS1-rearranged lung adenocarcinoma. ROS1D2033N confers crizotinib resistance, but remains highly sensitive to cabozantinib due to substantive differences in inhibitor binding modes. Treatment with cabozantinib resulted in significant tumor response in this patient. This is the first clinical example of overcoming acquired crizotinib-resistance with targeted therapy in a ROS1-rearranged malignancy and has immediate relevance for instructing ongoing clinical trials that are evaluating ROS1 inhibitors.Lenalidomide in combination with anti-CD20 monoclonal antibodies has clinical activity in lymphoproliferative disorders. In patients with chronic lymphocytic leukemia (CLL), lenalidomide also modulates T- and NK-cell function. Thirty-four patients with relapsed or refractory CLL were treated with combined lenalidomide and ofatumumab. Overall and complete response rates were 71% and 24%, respectively. The median progression-free survival was 16 months, and the estimated 5-year survival was 53%. Patients who achieved complete response had higher numbers and better-preserved function of T and NK cells before treatment. These findings emphasize the role of a competent immune system in successful cancer therapy.In EGFR-mutant NSCLC, resistance to first generation EGFR-TKIs and afatinib is mediated by the T790M resistance mutation in ∼60% of cases. The authors use two plasma-testing methodologies to evaluate detection of EGFR activating and T790M resistance mutations in matched tumor and plasma samples taken mostly from a phase 1 study of the third generation EGFR inhibitor rociletinib. Plasma assays identified T790M mutations missed by biopsy because of tumor heterogeneity or lack of adequate tumor tissue. These data suggest plasma testing will be a useful complement to tumor testing, particularly in the setting of acquired resistance.Predictive biomarkers of chemotherapy response in non-small cell lung cancer (NSCLC) are needed to better characterize patients who derive the greatest benefit. Bell and colleagues hypothesized that SMARCA4/BRG1, a gene that is commonly altered in NSCLC and other cancers, could be such a marker due to its established role in cisplatin sensitivity and DNA repair in vitro. Using mRNA expression data from patient samples enrolled in the JBR.10 randomized phase III trial, the authors were the first to demonstrate that NSCLCs harboring low SMARCA4 expression derive a large benefit from cisplatin-based adjuvant chemotherapy with a highly significant interaction test.
Highlights of This Issue
Journal: Clinical Cancer Research (2016)

Long-term survival is observed in a minority of melanoma patients after treatment with ipilimumab, while the benefit seems to be limited for others. Thus far, no biomarkers are routinely used to predict outcome. In a large multicenter study, Martens and colleagues identified a strong association between baseline frequencies of myeloid-derived suppressor cells and overall survival after start of ipilimumab, translating into a rationale for depletion/inhibition of these cells as therapeutic strategy. Moreover, they propose combination models, including one limited to broadly available routine markers, which strongly correlate with prognosis and suggest predictive impact for outcome after ipilimumab.Next-generation sequencing (NGS) has redefined the genetic landscape of diffuse large B-cell lymphoma (DLBCL) by identifying recurrent somatic mutations. To explore the feasibility of NGS in routine DLBCL patient management, Dubois and colleagues designed the Lymphopanel, a targeted panel based on 34 genes, with a distinct focus on the inclusion of actionable and prognostic targets. The Lymphopanel was informative for 96% of DLBCL patients and offered a clear depiction of DLBCL subtype molecular heterogeneity. The Lymphopanel is a clinically feasible tool, which can stratify patients according to their mutational profiles to afford novel personalized therapy opportunities.The immune checkpoint inhibitors (ICI) are proven to be effective in cancer immunotherapy; however, the efficacy may be further improved. Ma and colleagues examined the therapeutic effect of a combination of IL18 with ICIs using an animal model of disseminated tumor growth. The results showed that the combination markedly augmented the therapeutic effect. Notably, strong expansion of effector cells, including NK cells and CD8+ T cells, and reduction of Treg cells in the tumor microenvironments were observed. There was apparently no adverse effect augmented by the combination. The combination of IL18 and ICIs may be beneficial for cancer immunotherapy.To build on recent successes in cancer immunotherapy, we need to better understand how the immune system normally contends with cancer. Although the prognostic benefit of tumor-infiltrating T cells is well established, Kroeger and colleagues use innovative immunohistochemical analyses to reveal an equally important role for plasma cells (mature antibody-producing cells) in ovarian cancer. Remarkably, the authors found that the prognostic benefit of T cells is only seen in the presence of plasma cells, suggesting critical interactions between these lymphocyte subsets. The goal now is to develop immunotherapies that promote this potent combination of cellular and humoral responses in patients.
Highlights of This Issue
Journal: Clinical Cancer Research (2016)

Many immune mechanisms exist to prevent unchecked inflammation. Monjazeb and colleagues demonstrate that, after stimulatory immunotherapies such as radiotherapy + CpG, there is an onset of suppression orchestrated by indolamine-2,3-dioxygenase (IDO) that limits the antitumor effects of therapy. The addition of IDO blockade significantly improves efficacy by preventing this therapy-induced immune suppression in mouse and canine clinical trials. This study shows how a deeper understanding of the checks and balances of the immune system can further improve the efficacy of cancer immunotherapy and also demonstrates the potential of canines with spontaneous tumors as a highly relevant model of human malignancy.Hyperactive MYC signaling is an oncogenic driver for a large proportion of human tumors, but so far no MYC-directed therapeutic has been approved for clinical use. Polyamines are cationic chaperones that support MYC activities, and their homeostasis is critical to both initiating and maintaining the cancer phenotype. Evageliou and colleagues demonstrate therapeutics that deplete tumoral polyamines (such as DFMO, celecoxib, and SAM486), synergize to block tumor initiation, and regress established tumors in models of lethal childhood tumor neuroblastoma. These data strongly support the testing of such approaches in the clinic.EPI binds the N-terminal domain of an androgen receptor (AR) to block the transcriptional activities of full-length AR and constitutively active AR splice variants (AR-V). EPI is the first drug developed against AR NTD, and its prodrug is currently in clinical trials for prostate cancer patients failing abiraterone and/or enzalutamide, which have no effect on AR-V. Yang and colleagues show that EPI displays potent in vivo efficacy against enzalutamide-resistant tumors that are considered to be driven by AR-V and show that EPI blocks other known AR mechanisms of resistance. EPI may provide significant therapeutic benefit for patients with prostate cancer.Epithelial-to-mesenchymal transition is a complex process through which epithelial cancer cells acquire a reversible change in phenotype. Boufraqech and colleagues show that LOX transcriptionally regulates SNAI2 expression. SNAI2 knockdown recapitulates the phenotypic effects of LOX in vitro and in vivo, suggesting a LOX–SNAI2 axis in cancer progression. In addition, the effect of the LOX–SNAI2 axis in cancer progression is mediated by TIMP4 secretion SNAI2, and TIMP4 proteins are overexpressed in aggressive thyroid, breast, and colon cancer. These findings have important consequences for developing strategies to block this axis and control cancer progression.
Highlights of This Issue
Journal: Clinical Cancer Research (2016)

Martens and colleagues describe changes in circulating immune cells in metastatic melanoma patients treated with ipilimumab, a CTLA-4 inhibitor, and the impact on clinical outcome. Routine blood counts of T cells, Tregs, and MDSCs were performed in an international cohort of 82 melanoma patients. Changes in absolute lymphocyte counts, CD4+ T cells, and CD8+ T cells were associated with overall survival and clinical response. Increases in all three cell populations identified patients with excellent outcome. These changes reflect the positive mode of action of ipilimumab, underline the importance of the specific T cell response for immunologic tumor control, and represent surrogate marker candidates for outcome.Somatic mutations in the tyrosine kinase domain of HER2 may be an alternative mechanism to HER2 activation and affect breast cancer sensitivity toward HER2-targeted therapies. In this study by Zuo and colleagues, 1,248 primary tumors and 18 paired metastatic samples were sequenced for HER2 mutations. Functional analysis found that HER2 negative breast cancer with novel activating mutations may benefit from HER2-targeted therapies, while HER2-positive tumors harboring novel resistance mutations did not. These findings will help illustrate the potential clinical implications of HER2 somatic mutations and assist in identifying patients who would benefit from HER2-targeted therapies in choosing the most beneficial treatment.Lenalidomide, thalidomide and pomalidomide (LTP) are immunomodulatory agents for the treatment of multiple myeloma; however, they may increase the incidence of secondary primary malignancies, particularly with lenalidomide use in the maintenance setting. Jones and colleagues show that LTP are able to stimulate the Epstein-Barr virus (EBV) lytic cycle, both in vitro and in vivo, primarily by activating phosphoinositide 3-kinase signaling. This provides a potential mechanism through which use of LTP in immunocompromised patients could promote the development of EBV-associated malignancies, such as Hodgkin disease, through immune suppression, and could also provide a new approach for EBV-related cancers in combination with ganciclovir.Lumican is an extracellular matrix protein whose presence with primary pancreatic ductal adenocarcinoma (PDAC) tumors is associated with improved patient outcome. Kang and colleagues find that activated pancreatic stellate cells isolated from primary PDAC tumors secrete large amounts of lumican that augment adhesion and migration of activated pancreatic stellate cells in a collagen-rich environment. TGF-β inhibits lumican transcription and secretion in activated stellate cells through its canonical signaling pathway and binding of SMAD4 to novel SMAD-binding elements. These findings underscore the influential role of lumican within the stroma of localized PDAC and its impact on tumor biology and patient outcome.
Highlights of This Issue
Journal: Clinical Cancer Research (2016)

Stromal cell-derived cytokine B-cell activating factor (BAFF) confers a survival advantage for myeloma cells and is associated with more aggressive disease and worse outcome. Raje and colleagues report a phase 1 study of tabalumab, a BAFF neutralizing antibody, in combination with bortezomib in relapsed/refractory multiple myeloma patients. The results show the combination was well tolerated and demonstrated efficacy even in patients previously treated with bortezobib.Pazopanib plasma trough concentrations (Cmin) have previously been linked to progression free survival (PFS). In renal cell carcinoma, patients with a Cmin ≥20 mg/L had a PFS of 50.2 weeks compared with only 19.6 weeks in patients &lt;20 mg/L. Verheijen and colleagues conducted a clinical trial to individualize the dose of pazopanib based on Cmin. The dosing algorithm resulted in daily dosages of 400 to 1,800 mg. The results suggest individualized dosing is safe, feasible, and an additional 23% of patients reached a Cmin of ≥20 mg/L. These data support future prospective studies investigating the effect of individualized pazopanib dosing on PFS.With the rapid expansion of targeted therapeutics for the treatment of non-small cell lung cancer (NSCLC), the role of molecular phenotyping has never been more clinically relevant. Thompson and colleagues performed next-generation sequencing (NGS) of circulating tumor DNA (ctDNA) in 102 NSCLC patients, including 50 for whom sufficient tissue DNA was not obtainable, and identified 62 driver and resistance mutations. This is the largest prospective study to date using ctDNA NGS for NSCLC management highlighting the practical challenges in reliably achieving tissue molecular profiling and demonstrating the promise of ctDNA testing for real-time personalized cancer care.Soler and colleagues assessed the frequency of PI3K pathway activation in human pancreatic neuroendocrine tumor progression (PanNET) and in RIP1-Tag2 mice, a model of PanNETs. They investigated the therapeutic efficacy of inhibiting PI3K in RIP1-Tag2 mice using PI3K inhibitors and isoform-specific PI3K kinase-dead mutant mice. They report that human and mouse PanNETs show enhanced activation of the PI3K pathway compared with normal tissue and that selective inactivation of the p110α isoform is sufficient to block RIP1-Tag2 tumor progression and metastasis. Inhibition of p110α induces tumor cell death and compromises vessel growth.
Highlights of This Issue
Journal: Clinical Cancer Research (2016)

Multigene assays have been incorporated into the management of patients with node-negative hormone receptor-positive breast cancer for determining adjuvant treatment strategies. To compare prognostic accuracy of two multigene assays, Sestak and colleagues examined cross-stratification between Breast Cancer Index (BCI) and the 21-gene recurrence score (RS) in the TransATAC study. The findings show that BCI demonstrates increased prognostic accuracy versus RS. BCI restratified women with low and intermediate risk by RS into clinically relevant risk groups with significantly different risks of distant recurrence. These findings indicate that BCI may have potential impact to improve individualized risk stratification for patients with early-stage breast cancer.Dennison and colleagues evaluated the associative effects of breast cancer with the tumor microenvironment and its influence on tumor behavior. The reactive subtype of breast cancer, identified by reverse-phase protein arrays to have high expression of ECM proteins, was demonstrated to indicate a favorable outcome. The lowest risk tumors, typically ER+ER2− breast cancer, were more likely to have high expression of stromal proteins, high intratumoral stromal volume, and increased cell density within the stromal compartment.Antibody–drug conjugates (ADC) have become a promising anticancer agent. Ogitani and colleagues generated and evaluated a novel HER2-targeting ADC called DS-8201a, with a DNA topoisomerase I inhibitor. It showed potent antitumor activity against T-DM1-insensitive tumors and HER2 low-expressing tumors due to the different mechanism payload from T-DM1 and higher a drug-to-antibody ratio than T-DM1. Moreover, favorable pharmacokinetic and safety profiles in monkeys were observed. These data suggest that DS-8201a is an attractive and promising HER2-targeting ADC, which provides an additional treatment option for current HER2-targeting therapy.Antibody–drug conjugates directed at specific antigens preferentially expressed on cancer cells are gaining traction in the clinic. Here, Almhanna and colleagues perform the first-in-human phase 1 study investigating TAK-264 targeting guanylyl cyclase, a transmembrane cell-surface receptor expressed in many gastrointestinal cancers. The results demonstrate a manageable safety profile at the maximum tolerated dose, preliminary evidence of antitumor activity, and early signs of clinical benefit in patients with pancreatic, esophageal, and gastric carcinoma.
Highlights of This Issue
Journal: Clinical Cancer Research (2016)

BRAF and MEK inhibitors have improved the clinical management of BRAF-mutant melanoma; however, patients often develop drug resistance. MITF is a transcription factor required for melanoma formation. Rose and colleagues demonstrate that clinically approved MAPK inhibitors cause the MITF-dependent upregulation of GPNMB. GPNMB is the target of an antibody-drug conjugate (CDX-011) currently in clinical trials. Combining BRAF and/or MEK inhibitors with CDX-011 enhanced melanoma tumor regression and delayed emergence of acquired resistance when compared with treatment with MAPK pathway inhibitors alone. These findings support the initiation of clinical trials to assess the efficacy of MAPK pathway inhibitors combined with CDX-011 for the treatment of melanoma.Osswald and colleagues develop an in vivo two-photon microscopy approach to study blood brain barrier (BBB) permeability properties, tumor growth kinetics, and response to PI3K/mTOR inhibitors in metastatic melanoma of the brain. A BBB permeable inhibitor, but not an impermeable inhibitor, reduced the growth rate of impermeable metastases. These results provide evidence that nonpermeable brain micro- and macrometastases can effectively be targeted by drugs designed to cross the BBB.Patient-derived xenograft (PDX) models have been proved to be effective in prioritizing therapeutic regimens in personalized cancer medicine; however, establishing and testing transplantable tumorgrafts are expensive and time-consuming. In this study, Roife and colleagues developed an ex vivo drug efficacy testing method, Live Tissue Sensitivity Assay (LTSA), for patients with pancreatic ductal adenocarcionma. The test enables efficient testing of PDX tumor in 96-well plates against standard of care chemotherapeutic agents in 2 to 3 days. This system is highly reflective of patients' responses to conventional therapeutic agents and has significant potential for guiding personalized cancer treatment design.There is a pressing need for biomarkers to assist with the clinical management of brain tumor patients. The majority of WHO grade II–III gliomas express mutant forms of Isocitrate Dehydrogenases (IDH) 1 and 2, resulting in excessive production of D-2-Hydroxyglutarate (D-2HG) in the tumor cells. Kalinina and colleagues examined whether this oncometabolite is shed into the cerebrospinal fluid (CSF) and if it can potentially serve as a biomarker. Using mass spectrometry the authors demonstrated high levels of D-2HG in the CSF of IDH1-mutant glioma patients, suggesting that this assay may be developed into a clinical test for diagnosis, prognosis, and follow-up of glioma patients.
Highlights of This Issue
Journal: Clinical Cancer Research (2017)

To explore a novel molecularly targeted strategy that may abrogate or delay the emergence of antiestrogen resistance in hormone-dependent breast cancer, Mayer and colleagues conducted a phase Ib clinical trial of the PI3Kα-specific inhibitor, alpelisib, and the aromatase inhibitor, letrozole, in patients with ER+ metastatic breast cancers refractory to endocrine therapies. Study results show that the above combination was safe, tolerable, and active, particularly in those patients whose tumors harbored an activating mutation in PIK3CA. Phase II and III trials of alpelisib and endocrine therapy in patients with ER+ breast cancer are ongoing.Clinical management of early-stage lung cancer is becoming crucial due to recent activation of cancer prevention and screening programs. The availability of prognostic biomarkers for patients with early-stage lung cancer (stage I) is paramount for therapy optimization. Dama and colleagues developed a molecular test easily implementable in a routine laboratory setting to diagnose an aggressive subtype of stage I lung adenocarcinoma. Remarkably, a comprehensive analysis of genetic, epigenetic, and proteomic profiles identified molecular features in this subtype that are peculiar in metastatic lung cancer. These findings also suggest new possibilities for tailored therapies in patients with early-stage lung cancer.Human Ether-à-go-go-related gene (hERG) encodes a voltage-gated potassium channel that is overexpressed in glioblastoma (GBM) cell lines. Pointer and colleagues discovered that high hERG expression in GBM is correlated with poor patient survival. Furthermore, patients with high hERG-expressing tumors who also received drugs with incidental hERG inhibitory activity experienced significantly improved median survival compared with those who did not receive a hERG blocker. This study establishes hERG as a new GBM biomarker and the rationale for targeting clinical trials of hERG inhibitors for the subset of high hERG-expressing GBM patients.The presence of stem-like cells and the intratumor heterogeneity are key features for resistance to anticancer treatments, including targeted therapy. In colorectal cancer (CRC) EphA2 overexpression has been linked to stem-like properties of cells and tumor malignancy. De Robertis and colleagues characterized murine homogeneous EphA2high CRC cell subpopulation, unveiling a novel potential molecular signature related to EphA2/EGFR pathway. These preclinical findings strongly correlated with clinical outcome and cetuximab responsiveness. Because anti-EGFR drug resistance remains a critical issue in treating CRC, this study may provide new potential biomarkers and therapeutically actionable kinase targets in the EphA2/Efna1/EGFR/mir-26b/mir-200a linked pathways.